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Analysis of the effect of IDO inhibition on activation of the aryl hydrocarbon receptor pathway in bladder cancer

Funder: São Paulo Research Foundation

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Bladder cancer (BC) is among the most common urinary system. Although the most frequent form is non-invasive, many of these cases evolve to invasive form. Indoleamine 2,3-dioxygenase (IDO) is an enzyme expressed at sites where immunomodulation is required, including the maternal-fetal interface, where the presence of IDO protects the semihalogen embryo. Because IDO is expressed in some cancers, it is believed to promote immune escape from the tumor. IDO exerts its effects through tryptophan depletion in the microenvironment, with consequent formation of quinurenine and its derivatives and is associated with AHR (aryl hydrocarbon receptor).In BC, its role has not been completely elucidated, but we believe that IDO also participates in non-immunological events. Multiple mechanisms have been implicated in tumor invasion and metastasis, including the mesenchymal-epithelial transition (TEM). While there is controversy about the role of IDO in cancer, molecules that can modulate IDO-mediated pathways are seen as promising for cancer treatment. In this context, 1-methyl-D-tryptophan (MT), a competitive inhibitor of IDO, has been extensively studied as an anticancer agent. However, more recent studies show that MT can lead to AHR activation leading to activation of pathways initially modulated by quinurenins. Thus our proposal is to compare the cellular mechanism of action of MT with a new proposed IDO inhibitor, INCB024360-Analog 5l, validating its potential as a more specific and clinically viable inhibitor of IDO in BC.RT4 and T24 cells (representative non-muscle invasive and muscle-invasive BC) are cultured routinely in our laboratory. For the treatment of cells with MT or INCB, cells will be maintained in RPMI 1640 medium supplemented with 10% SFB and antibiotics containing MT or INCB. Real-time PCR will be used to evaluate the expression of the AHR gene and the gene involved in its activation CYP1A1 (a marker of AHR receptor activation). In addition, the results will be compared to assess whether or not there was a difference in response between cell lines. As expected results, this study may reveal whether INCB024360-Analog 5l promotes different responses to MT, classic IDO inhibitor in non-invasive and muscle-invasive BC cells, serving as a better option in inhibiting IDO, and whether it has an influence on AHR activation pathway (AU)
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